Neonatal Hepatic Drug Elimination

Abstract

After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

Prenatal alcohol exposure, blood alcohol concentrations and alcohol elimination rates for the mother, fetus and newborn

“…The level of CYP2E1 enzyme was found to increase significantly at birth, regardless of gestational age with notable increase on the first post natal day. 29 The capacity of the kidneys to excrete ethanol also increases after birth. Hemodynamic changes occur around the time of birth that causes a 50 to 100% increase in glomerular filtration rate during the 1st week of life.…”

Cytochrome P450 Genetic Polymorphism in Neonatal Drug Metabolism: Role and Practical Consequences towards a New Drug Culture in Neonatology

“…In humans, the most important isoenzymes for drug metabolism are localized in the liver, seven isoenzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP206 CYP3A4) being responsible for the metabolism of more than 95% of drugs (16). CYP450 isoforms involved in drug metabolism are also present in kidney, lung, brain, breast, prostate and in the small intestine (17).…”

“…CYP2C is negligible in the fetal liver, its expression starts at I day of postnatal age, begins to rise at 1 week, and in the second week reaches a plateau at 40% of adult levels. CYP2D6 is negligible in the fetus; its expression starts at birth, reaching a plateau at 1 month (16). CYP3A4 represents 30-40% of the total CYP content in human adult liver and in small intestine mucosa cells.…”

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

“…Yet, the presence and activity of CYP2E1 in developing liver remains a topic of debate [79]. Furthermore, it is known that the expression of adult CYP isoforms, including CYP1A2, CYP12C, CYP12D6, and CYP3A4, mainly occurs after birth [80]. This leads to important differences in metabolic capacity between embryonic/fetal liver and adult liver, which could suggest that APAP exhibits its hepatotoxicity through an alternative mode of action within developing hepatocytes.…”